Debulking of the Femoral Stem in a Primary Total Hip Joint Replacement: A Novel Method to Reduce Stress Shielding.

In current-generation designs of total primary hip joint replacement, the prostheses are fabricated from alloys. The modulus of elasticity of the alloy is substantially higher than that of the surrounding bone. This discrepancy plays a role in a phenomenon known as stress shielding, in which the bone bears a reduced proportion of the applied load. Stress shielding has been implicated in aseptic loosening of the implant which, in turn, results in reduction in the in vivo life of the implant. Rigid implants shield surrounding bone from mechanical loading, and the reduction in skeletal stress necessary to maintain bone mass and density results in accelerated bone loss, the forerunner to implant loosening. Femoral stems of various geometries and surface modifications, materials and material distributions, and porous structures have been investigated to achieve mechanical properties of stems closer to those of bone to mitigate stress shielding. For improved load transfer from implant to femur, the proposed study investigated a strategic debulking effort to impart controlled flexibility while retaining sufficient strength and endurance properties. Using an iterative design process, debulked configurations based on an internal skeletal truss framework were evaluated using finite element analysis. The implant models analyzed were solid; hollow, with a proximal hollowed stem; FB-2A, with thin, curved trusses extending from the central spine; and FB-3B and FB-3C, with thick, flat trusses extending from the central spine in a balanced-truss and a hemi-truss configuration, respectively. As outlined in the International Organization for Standardization (ISO) 7206 standards, implants were offset in natural femur for evaluation of load distribution or potted in testing cylinders for fatigue testing. The commonality across all debulked designs was the minimization of proximal stress shielding compared to conventional solid implants. Stem topography can influence performance, and the truss implants with or without the calcar collar were evaluated. Load sharing was equally effective irrespective of the collar; however, the collar was critical to reducing the stresses in the implant. Whether bonded directly to bone or cemented in the femur, the truss stem was effective at limiting stress shielding. However, a localized increase in maximum principal stress at the proximal lateral junction could adversely affect cement integrity. The controlled accommodation of deformation of the implant wall contributes to the load sharing capability of the truss implant, and for a superior biomechanical performance, the collared stem should be implanted in interference fit. Considering the results of all implant designs, the truss implant model FB-3C was the best model.

Effect of recombinant human thyroid stimulating hormone on long-term salivary gland dysfunction in thyroid cancer patients treated with radioactive iodine. A systematic review.

Adjuvant radioactive iodine (RAI) is administered to thyroid cancer patients following thyroidectomy for remnant tissue ablation and metastatic disease management. Patients are prepared with thyroid hormone withdrawal (THW) or recombinant human thyroid stimulating hormone (rhTSH). Long-term salivary gland dysfunction (LT-SGD) is a common, dosage-dependent, RAI adverse effect. Although rhTSH preparation seems to reduce LT-SGD, this effect could be due to lower RAI activity generally used in rhTSH-prepared patients. Therefore, this meta-analysis investigated the effect of preparation type on LT-SGD development. Literature search (PubMed, Medline, EmBase, Cochrane, Web of Science, LILACS, Google Scholar) was performed four times (January-November 2022) and studies reporting LT-SGD incidence ≥1 year after RAI in patients prepared with rhTSH/THW were identified. The LT-SGD risk ratio (RR) was estimated with various models considered for sensitivity analysis (fixed-effect, random-effects, study-quality adjusted, publication-bias adjusted, individual-patient-data meta-analysis adjusted for RAI). Subgroup analysis according to RAI activity (<3.7/≥3.7 GBq) also was performed. Literature search resulted in five studies (321 rhTSH, 632 THW patients). The pooled RRs according to various models were 0.65 (95% confidence interval -95CI, 0.49-0.86; fixed-effect); 0.62 (95CI, 0.38-1.02; random-effects); 0.72 (95CI, 0.54-0.96; quality adjusted); 0.76 (95CI, 0.58-0.99; publication-bias adjusted); 0.0.80 (95CI, 0.55-1.14; individual-patient-data meta-analysis). The pooled RRs stratified for RAI activity were 0.26 (95CI, 0.05-1.30) for <3.7 GBq; 0.75 (95CI, 0.57-0.98) for ≥3.7 GBq. The number of patients needed to be prepared with rhTSH to prevent one case of LT-SGD ranged between seven and thirty-seven. There is moderate-quality scientific evidence that rhTSH preparation may consistently protect salivary gland function.

Chemosensory loss in COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 virus quickly spread globally, infecting over half a billion individuals, and killing over 6 million*. One of the more unusual symptoms was patients' complaints of sudden loss of smell and/or taste, a symptom that has become more apparent as the virus mutated into different variants. Anosmia and ageusia, the loss of smell and taste, respectively, seem to be transient for some individuals, but for others persists even after recovery from the infection. Causes for COVID-19-associated chemosensory loss have undergone several hypotheses. These include non-functional or destroyed olfactory neurons and gustatory receptors or of their supporting cells, disruption of the signaling protein Neuropilin-1, and disruption in the interaction with semaphorins, key molecules in the gustatory and olfactory axon guidance. The current paper will review these hypotheses and chart out potential therapeutic avenues.

Pandemics and education: A historical review.

Major pandemics have tremendous effects on society. They precipitated the early decline of the Western Roman Empire and helped spread Christianity. There are countless such examples of infectious diseases altering the course of history. The impact of epidemics on education however is less well documented. This present historical account of the past 800 years looks specifically at how some aspects of education were shaped from the early medieval epidemics such as leprosy and the Black Plague to the Spanish Flu and COVID-19. Leprosy changed religious education, and the Black Plague may have contributed to the rise of medical schools, hospitals, public health education, and led to the implementation of lazarettos and the quarantine. The smallpox epidemic helped usher in public health education for immunization, while the 1918 Spanish Flu precipitated the rise of education by correspondence, and recently COVID-19 has catapulted remote digital learning to the forefront of higher education.

Disorder at the Start: The Contribution of Dysregulated Translation Initiation to Cancer Therapy Resistance.

Translation of cellular RNA to protein is an energy-intensive process through which synthesized proteins dictate cellular processes and function. Translation is regulated in response to extracellular effectors and availability of amino acids intracellularly. Most eukaryotic mRNA rely on the methyl 7-guanosine (m7G) nucleotide cap to recruit the translation machinery, and the uncoupling of translational control that occurs in tumorigenesis plays a significant role in cancer treatment response. This article provides an overview of the mammalian translation initiation process and the primary mechanisms by which it is regulated. An outline of how deregulation of initiation supports tumorigenesis and how initiation at a downstream open reading frame (ORF) of Tousled-like kinase 1 (TLK1) leads to treatment resistance is discussed.

Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer.

Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable, TAT-fusion Tousled-like kinase 1B (TLK1B) protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However, similar to most radioprotectors, TLK1B can carry the risk of limiting cancer treatment efficacy. The central goal of the study was, therefore, to reengineer TLK1B as a selective radioprotector of normal cells. Degradation of the extracellular matrix by proteases such as matrix metalloproteinases (MMPs) is a hallmark of aggressive tumors. Increased expression of membrane type 1-MMP (MT1-MMP; also called MMP14) is observed in a variety of cancers including head and neck squamous cell carcinoma (HNSCC). To limit TLK1B transduction to normal cells, we rendered the protein susceptible to MT1-MMP cleavage on the premise that high expression of MT1-MMP on the cell surface of HNSCC will suppress TLK1B internalization. Two optimal MT1-MMP-sensitive sequences (MS) were identified that when incorporated in TAT-TLK1B excluded its cellular entry in HNSCC, SCC40, but not immortalized salivary acinar cells, NS-SV-AC. Importantly, administration of MS-harboring TAT-TLK1B did not affect the sensitivity of tumors to radiation in a nude mouse xenograft tumor model. We conclude that a MMP-sensitive TLK1B can be an attractive therapeutic to allay salivary radiotoxicity without compromising cancer treatment efficacy.

Cross-contamination of the human salivary gland HSG cell line with HeLa cells: A STR analysis study.

OBJECTIVES: The human salivary gland (HSG) cell line, labeled as a submandibular ductal cell line, is commonly used as in vitro models to study radiation therapy, Sjögren's syndrome, pleomorphic adenoma, mucocele, epithelial-to-mesenchymal transition, and epigenetics. However, the American Type Culture Collection (ATCC) has recently released a list of cross-contaminated cell lines that included HSG. Despite this notice, some research laboratories still use HSG as a salivary cell model. Therefore, this study examined the authenticity of HSG sampled from three different laboratories. METHODS: DNA was extracted from HSG and additional salivary cell lines (NS-SV-AC, NS-SV-DC, A253, HSY) and submitted for cell line authentication with short tandem repeat (STR) analysis. RESULTS: All HSG samples had STR profiles indicating >80% match with HeLa in both the ATCC and Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) databases. This confirmed that HSG sampled from three different laboratories and HSY shared a common ancestry (host) with HeLa, whereas NS-SV-AC, NS-SV-DC, and A253 had unique STR profiles. CONCLUSION: Short tandem repeat analysis revealed that HSG was contaminated by the HeLa cell line. Furthermore, because genotyping of the original HSG cell line was not performed during its establishment, it will be difficult to authenticate an uncontaminated sample of HSG.

Sildenafil Transiently Delays Early Alveolar Healing of Tooth Extraction Sockets.

Bone is a unique tissue that has the ability to repair itself and return to full function. Bone regeneration is a well synchronized biological process that recapitulates embryonic bone development. The establishment of a functional vascular supply has been shown to be essential for proper ossification of newly deposited bone, and impaired angiogenesis as in advanced age, diabetes, and anti-cancer treatments affect bone repair. Endothelial Guanosine, 3', 5'-Cyclic Monophophate(cGMP) is known to support angiogenesis, and sildenafil, a Phosphodiesterase 5 (PDE5) antagonist, prevents cGMP hydrolysis and thereby, promotes the formation of new blood vessels. Since the development of functional vascular networks is critical to bone repair, we investigated the effects of sildenafil on early alveolar bone regeneration following exodontia. Our results demonstrate that per-oral administration of sildenafil (10 mg/kg/day) in rats delays the dissolution and replacement of the sanguine clot with granulation tissue. As a result, the number of replicating cells, a hallmark of regenerating tissue, observed on day 4 was remarkably lower in sildenafil-treated animals than their control counterparts (mean±SD; control: 47.35±9.21; sildenafil: 11.47±5.14). Similarly, cells expressing transcription factor Cbfa-1/Runx2 and osteopontin, markers of differentiating osteoblasts, were fewer in treated animals (mean±SD; control: 83.18 ± 4.60; sildenafil: 13.77 ± 4.63). Treatment with hydrolysis-resistant cyclic GMP (cGMP) showed findings similar to sildenafil-treated animals suggesting a negative impact of cGMP on early inflammatory phase of bone healing. However, histological differences were not significant between the 2 groups on day 8. Based on these findings, we conclude that sildenafil temporarily retards early events in alveolar bone healing.

DNA damage response and repair data with pharmacological modulators of Tousled.

Human Tousled kinase 1 (TLK1) plays an important role in chromatin remodeling, replication, and DNA damage response and repair. TLK1 activity is immediately, but transiently, downregulated after genotoxic insult, and its recovery is important for exit from checkpoint arrest and cell survival after radiation. The data in this article compliments research presented in the paper titled, "Tousled kinase activator, gallic acid, promotes DNA repair and suppresses radiation cytotoxicity in salivary gland cells" [1]. The identification of small molecule activators and inhibitors of TLK1 provided an opportunity to pharmacologically alter the protein׳s activity to elucidate its role in DNA damage response pathways. TLK1 effectors, gallic acid (GA) and thioridazine (THD) activate and inhibit the kinase, respectively, and the data report on the impact of these compounds and the significance of TLK1 to DNA break repair and the survival of human salivary acinar cells.

Retroductal Submandibular Gland Instillation and Localized Fractionated Irradiation in a Rat Model of Salivary Hypofunction.

Normal tissues that lie within the portals of radiation are inadvertently damaged. Salivary glands are often injured during head and neck radiotherapy. Irreparable cell damage results in a chronic loss of salivary function that impairs basic oral activities, and increases the risk of oral infections and dental caries. Salivary hypofunction and its complications gravely impact a patient's comfort. Current symptomatic management of the condition is ineffective, and newer therapies to assuage the condition are needed. Salivary glands are exocrine glands, which expel their secretions into the mouth via excretory ducts. Cannulation of these ducts provides direct access to the glands. Retroductal delivery of a contrast agent to major salivary glands is a routine out-patient procedure for diagnostic imaging. Using a similar procedure, localized treatment of the glands is feasible. However, performing this technique in preclinical studies with small animals poses unique challenges. In this study we describe the technique of retroductal administration in rat submandibular glands, a procedure that was refined in Dr. Bruce Baum's laboratory (NIH)(1), and lay out a procedure for local gland irradiation.

Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells.

Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS-SV-AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS-SV-AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells.

Promising Gene Therapeutics for Salivary Gland Radiotoxicity.

More than 0.5 million new cases of head and neck cancer are diagnosed worldwide each year, and approximately 75% of them are treated with radiation alone or in combination with other cancer treatments. A majority of patients treated with radiotherapy develop significant oral off-target effects because of the unavoidable irradiation of normal tissues. Salivary glands that lie within treatment fields are often irreparably damaged and a decline in function manifests as dry mouth or xerostomia. Limited ability of the salivary glands to regenerate lost acinar cells makes radiation-induced loss of function a chronic problem that affects the quality of life of the patients well beyond the completion of radiotherapy. The restoration of saliva production after irradiation has been a daunting challenge, and this review provides an overview of promising gene therapeutics that either improve the gland's ability to survive radiation insult, or alternately, restore fluid flow after radiation. The salient features and shortcomings of each approach are discussed.